Von Willebrand Disease (VWD)
Conditions
Brief summary
The main aim of the study is to check effectiveness of rVWF (vonicog alfa) prophylaxis based on the annualized bleeding rate (ABR) of spontaneous (not related to trauma) bleeding episodes in pediatric and adult participants during the first 12 months on study treatment. The participants will be treated with rVWF for a maximum of 3 years. Their von Willebrand Disease will be treated according to Investigational product (IP) dosing directions.
Interventions
BIOLOGICALrVWF
Recombinant von Willebrand factor
BIOLOGICALrFVIII
Recombinant Factor VIII
Sponsors
Takeda Development Center Americas, Inc.
Baxalta now part of Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The participant will not be considered eligible for the study without meeting all of the criteria below. Participants who have completed Study 071301 or Study 071102 (or participants who have completed the surgery arm treatment in Study 071102 and want to continue to receive on-demand (OD) treatment) and are willing to immediately transition into this study, must meet the following 2 criteria to be eligible for this study: * If female of childbearing potential, has a negative blood/urine pregnancy test at screening and agrees to employ highly effective birth control measures for the duration of the study. * Participant and/or legally authorized representative is willing and able to comply with the requirements of the protocol. New participants (Cohort 4) who meet the above 2 and ALL the following additional criteria are eligible for this study: \- Participant has a documented diagnosis of severe von Willebrand disease (VWD) (baseline von Willebrand factor: Ristocetin cofactor (VWF:RCo) \<20 International Units per deciliter \[IU/dL\]) with a history of requiring substitution therapy with von Willebrand factor (vWF) concentrate to control bleeding: * Type 1 (VWF:RCo \<20 IU/dL) or, * Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or, * Type 3 (Von Willebrand factor antigen (VWF:Ag) less than or equal to (\<=) 3 IU/dL). Diagnosis is confirmed by genetic testing and multimer analysis, documented in participant history or at screening. * Participant has been receiving OD therapy with VWF products for at least 12 months, and prophylactic treatment is recommended by the investigator. * Participant has greater than or equal to (\>=) 3 documented spontaneous bleeds (not including menorrhagia) requiring VWF treatment during the past 12 months. * Participant has available records that reliably evaluate type, frequency, and treatment of bleeding episodes for at least 12 months preceding enrollment; up to 24 months of retrospective data should be collected if available. * Participant is \>=12 years old at the time of screening and has a body mass index \>=15 but \<40 kilogram per meter square (kg/m\^2).
Exclusion criteria
The participant will be excluded from the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Spontaneous Annualized Bleeding Rate (sABR) | Up to 12 months | sABR was derived as \[number of treated bleeds\] / \[duration in years\]. Bleeds with unknown causality were considered as spontaneous. Bleeds were categorized based on the investigator assessment of cause. sABR during the first 12 months of prophylactic treatment with rVWF (vonicog alfa) was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Based on Severity of TEAEs | Up to 5.8 years | An AE is defined as any untoward medical occurrence in a participant administered IP that does not necessarily have a causal relationship with the treatment. TEAE was defined as any AE that started after the first administration of study drug in this continuation study. Severity of TEAEs was determined by following definitions: Mild: No limitation of usual activities; Moderate: Some limitation of usual activities and may required therapeutic intervention; Severe: Inability to carry out usual activities with sequelae, which required therapeutic intervention. Number of participants with TEAEs based on severity of TEAEs were reported. |
| Number of Participants Based on Causality of TEAEs | Up to 5.8 years | An AE is defined as any untoward medical occurrence in a participant administered IP that does not necessarily have a causal relationship with the treatment. TEAE was defined as any AE that started after the first administration of study drug in this continuation study. A physician/investigator made the assessment of relationship to investigational product for each AE. Number of participants with TEAEs based on causality were reported. |
| Number of Participants With Thromboembolic Events | Up to 5.8 years | Thromboembolism defined as formation of a clot (thrombus) in a blood vessel that breaks loose, is carried by the blood stream and could plug another vessel. Number of participants with thromboembolic events as TEAEs of special interest were reported. |
| Number of Participants With Hypersensitivity Reactions | Up to 5.8 years | Hypersensitivity (also called hypersensitivity reaction or intolerance) defined as undesirable reactions produced by the normal immune system, including allergies and autoimmunity. Potential hypersensitivity events were identified by broad search criteria and then medically assessed. Number of participants with hypersensitivity reactions as TEAEs of special interest was calculated. |
| Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (VWF) | Up to 5.8 years | Three functional VWF assays for von Willebrand factor collagen binding (VWF:CB), von Willebrand factor: Ristocetin Cofactor (VWF:RCo) and von Willebrand factor VIII B (VWF:FVIIIB) were used to test the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and VWF:FVIIIB activities were measured by assays based on the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the Bethesda assay). Only confirmed neutralizing anti -VWF antibodies were considered inhibitors. Number of participants who developed neutralizing antibodies to rVWF were assessed. |
| Number of Participants Who Developed Neutralizing Antibodies to Factor VIII (FVIII) | Up to 5.8 years | Three functional VWF assays for von Willebrand factor collagen binding (VWF:CB), von Willebrand factor: Ristocetin Cofactor (VWF:RCo) and von Willebrand factor VIII B (VWF:FVIIIB) were used to test the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and VWF:FVIIIB activities was measured by assays based on the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the Bethesda assay). Only confirmed neutralizing anti -VWF antibodies were considered inhibitors. Number of participants who developed neutralizing antibodies to FVIII were assessed. |
| Number of Participants Who Developed Total Binding Antibodies to Von Willebrand Factor (VWF) | Up to 5.8 years | The presence of total binding anti-VWF antibodies was determined by an enzyme-linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin (Ig) antibodies (IgG, IgM and IgA). Number of participants who developed of total binding antibodies to rVWF were assessed. |
| Number of Participants Who Developed Total Binding Antibodies to Factor VIII (FVIII) | Up to 5.8 years | Binding antibodies against FVIII were analyzed using a proprietary enzyme immunoassay. Number of participants who developed of total binding antibodies to FVIII were assessed. |
| Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins | Up to 5.8 years | Total Ig antibodies (IgG, IgA, IgM) against CHO protein were analyzed using ELISA. Number of participants who developed binding antibodies to CHO proteins were assessed. |
| Number of Participants Who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG) | Up to 5.8 years | Detection and quantification of IgG antibodies originating from human plasma that were directed against mouse-IgG (HAMA: human anti- mouse antibodies) were assessed using ELISA (Medac, Hamburg, Germany). Number of participants who developed binding antibodies to Mouse IgG were assessed. |
| Number of Participants Who Develop Binding Antibodies to Recombinant Furin (rFurin) | Up to 5.8 years | Total Ig antibodies (IgG, IgA, IgM) against human furin were analyzed using ELISA. Number of participants who developed binding antibodies to rFurin were assessed. |
| Number of Participants With Clinically Significant Changes in Vital Signs | Up to 5.8 years | Vital signs included blood pressure (systolic and diastolic), pulse rate, respiratory rate and body temperature. Number of participants with clinically significant change from baseline in vital signs were assessed. |
| Number of Participants With Clinically Significant Changes in Laboratory Parameters | Up to 5.8 years | Clinical laboratory parameters included serum chemistry, hematology and urinalysis assessments. Number of participants with clinically significant change from baseline in clinical laboratory parameters were assessed. |
| Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment | Up to 5.8 years | sABR was derived as \[number of treated bleeds\] / \[duration in years\]. Bleeds with unknown causality were considered as spontaneous. Bleeds were categorized based on the investigator assessment of cause. sABR during prophylaxis treatment with rVWF (vonicog alfa) while enrolled in the study were reported. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Up to 5.8 years | An adverse event (AE): any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to medicinal product. TEAE was defined as any AE that started after the first administration of study drug in this continuation study. Serious TEAEs: any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is medically important. |
| Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | Up to 5.8 years | The sABR was the number of spontaneous bleeds divided by the observation period in years, where an observation period = (date of completion/termination-date of first dose+1)/365.2425. sABR was categorized based on number of BEs as 0, greater than (\>) 0 through 2, \>2 through 5, \>5 during the prophylactic treatment with rVWF (vonicog alfa). Bleeding at multiple locations related to the same injury was counted as single BE. BEs of unknown cause were counted as spontaneous bleeds. Number of participants categorized based on sABR during prophylactic treatment with rVWF (vonicog alfa) were reported. |
| Time to First Bleeding Event on Prophylaxis Treatment | Up to 5.8 years | Time to event estimates and confidence intervals obtained from Kaplan-Meier analysis. Participants with 0 bleeds during each study period were censored at the date of the last day in that study period. |
| Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Up to 5.8 years | sABR was derived as \[number of treated bleeds\] / \[duration in years\]. sABR for BEs based on location of bleeding: Skin, Muscle, Mucosal Nasal, Mucosal Oral, Joint, Gastrointestinal (GI), Menstrual/Heavy Menstrual, Venipuncture Site, Soft Tissue, Body Cavity, Hematuria, Central Nervous System (CNS) and Other, while on prophylactic treatment with rVWF (vonicog alfa) were reported. |
| Number of Participants Who Achieved Transfusion-free Maintenance of Hemoglobin Levels | Up to 5.8 years | Transfusion free maintenance of hemoglobin levels during prophylactic treatment with rVWF (vonicog alfa) were reported. |
| Total Number of Infusions During Prophylactic Treatment | Up to 5.8 years | Total number of infusions during prophylactic treatment with rVWF (vonicog alfa) were reported. |
| Average Number of Infusions Per Week During Prophylactic Treatment | Up to 5.8 years | Average number of infusions per week during prophylactic treatment with rVWF (vonicog alfa) were reported. |
| Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment | Up to 5.8 years | For each participant, the body weight-adjusted dose (IU/kg) was derived as the number of units of rVWF infused (IU) divided by the last available body weight (kilogram \[kg\]) prior to the infusion. Total weight adjusted consumption of rVWF (vonicog alfa) per participant during prophylactic treatment with rVWF (vonicog alfa) was reported as International Units per kilogram (IU/kg). |
| Change From Baseline in Ferritin Levels Over Time | Up to 5.8 years | Change from baseline in ferritin levels over time during prophylactic treatment with rVWF (vonicog alfa) were reported. Baseline Ferritin lab assay for rollover participants in cohorts 1, 2 and 3 were not mandatory per protocol at the Screening Visit of this study as the results from End of Study (EOS) visit of parent studies were expected to be utilized for rollover cohorts 1-3. However, many participants in cohort 1 did not have this data collected at EOS Visit of parent study 071301 and no participant in cohorts 2 and 3 had this data collected at EOS Visit of parent studies 071301 and 071102. |
| Overall Hemostatic Efficacy Rating | Initial 12 months of study | Overall Hemostatic Efficacy Rating at resolution of bleed with respect to treatment of BEs for initial 12 months of study in OD cohorts. Hemostatic efficacy for treatment of BEs was rated on 4-point Likert scale as:excellent=full relief of pain&cessation of objective signs of bleeding after single infusion,no additional infusion is required for control of bleeding&administration of further infusion to maintain hemostasis would not affect scoring;good=definite pain relief&/or improvement in signs of bleeding after single infusion,possibly requires \>2 infusions for complete resolution&administration of further infusion to maintain hemostasis would not affect scoring;fair=probable&/or slight relief of pain&slight improvement in signs of bleeding after single infusion,required multiple infusions for complete resolution;none=no improvement of signs/symptoms or conditions worsen.Missing=number of unique BEs without any overall hemostatic efficacy rating at resolution of breakthrough BE. |
| Number of Infusions of Vonicog Alfa | Up to 5.8 years | Number of infusions of rVWF (vonicog alfa) utilized to treat BEs during OD treatment while enrolled in the study were reported. |
| Number of Infusions of ADVATE | Up to 5.8 years | Number of infusions of ADVATE (rFVIII, octocog alfa) utilized to treat BEs during OD treatment while enrolled in the study were reported. |
| Weight-adjusted Consumption of Vonicog Alfa Per Bleeding Episode | Up to 5.8 years | Weight-adjusted consumption (IU/kg) was derived as the total units infused (IU) divided by the last available body weight (kg) prior to the infusion. Weight-adjusted consumption of rVWF (vonicog alfa) per bleeding episode during OD treatment while enrolled in the study were reported. |
| Weight-adjusted Consumption of ADVATE Per Bleeding Episode | Up to 5.8 years | Weight-adjusted consumption (IU/kg) was derived as the total units infused (IU) divided by the last available body weight (kg) prior to the infusion. Weight-adjusted consumption of ADVATE (rFVIII, octocog alfa) per bleeding episode during OD treatment while enrolled in the study were reported. |
| Number of Participants Categorized Based on Weekly Number of Infusions | Up to 5.8 years | Categorized as ≥ 0 to \< 1 infusion per week, ≥ 1 to \< 2 infusions per week, ≥ 2 to \< 3 infusions per week, ≥ 3 infusions per week. The number of participants categorized based on number of infusions per week during prophylactic treatment with rVWF (vonicog alfa) were reported. |
Countries
Austria, France, Germany, Italy, Netherlands, Russia, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
Participants took part in the study at 23 investigative sites globally from 1 April 2019 to 30 January 2025.
Pre-assignment details
A total of 38 participants with diagnosis of Von Willebrand disease were enrolled. Only participants who received treatment in study(N=35) were included in analysis. These participants received recombinant von Willebrand factor (rVWF) \[vonicog alfa\], 50±10 international units per kilogram (IU/kg),intravenous(IV) infusion in either prophylaxis or on demand cohorts. Some participants received supportive treatment with ADVATE for treating bleeding episodes (BEs) if deemed necessary by investigator.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Prophylaxis Adult participants who transitioned from the phase 3 prophylaxis parent study 071301 (NCT02973087) received the same prophylactic dose, 50±10 IU/kg, IV infusion of vonicog alfa twice weekly as in parent study 071301. | 10 |
| Cohort 2: Prophylaxis Adult participants who transitioned from parent study 071301 (NCT02973087) with no clinically significant BE for the past 6 months started this continuation study at a lower dose/frequency of vonicog alfa once weekly or twice weekly prophylactic dose, 50±10 IU/kg, IV infusion compared to the dose received (50±10 IU/kg, IV infusion, thrice weekly) in parent study 071301. | 1 |
| Cohort 3: Prophylaxis Adolescent participants (aged 12 to \<18 years) who transitioned from the phase 3 OD and surgery parent study 071102 (NCT02932618) switched from receiving vonicog alfa OD treatment to receiving prophylactic dose of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study. | 1 |
| Cohort 4: Prophylaxis Newly enrolled adult and adolescent (aged 12 to \<18 years) participants who switched from OD treatment with Von Willebrand Factor (VWF) products started 50±10 IU/kg, IV infusion once weekly prophylaxis with vonicog alfa in this continuation study. | 5 |
| Cohort 5: On Demand Pediatric participants of all ages from parent study 071102 (NCT02932618) continued receiving OD treatment of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study. | 16 |
| Cohort 6: On Demand Adult participants from parent study 071301 (NCT02973087) switched back from prophylactic treatment in study 071301 to OD treatment of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study. | 2 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Site Closed by Sponsor | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Cohort 3: Prophylaxis | Cohort 2: Prophylaxis | Cohort 1: Prophylaxis | Cohort 4: Prophylaxis | Cohort 5: On Demand | Cohort 6: On Demand |
|---|---|---|---|---|---|---|---|
| Age, Customized >=12 to <18 years | 9 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 6 Participants | 0 Participants |
| Age, Customized >=18 years | 18 Participants | 0 Participants | 1 Participants | 10 Participants | 3 Participants | 2 Participants | 2 Participants |
| Age, Customized >=6 to <12 years | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 0 Participants |
| Age, Customized <6 years | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 1 Participants | 0 Participants | 8 Participants | 5 Participants | 14 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 30 Participants | 1 Participants | 0 Participants | 9 Participants | 4 Participants | 14 Participants | 2 Participants |
| Sex: Female, Male Female | 17 Participants | 0 Participants | 1 Participants | 4 Participants | 2 Participants | 9 Participants | 1 Participants |
| Sex: Female, Male Male | 18 Participants | 1 Participants | 0 Participants | 6 Participants | 3 Participants | 7 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 1 | 0 / 1 | 0 / 2 | 0 / 3 | 0 / 3 | 0 / 5 | 0 / 6 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 8 / 10 | 1 / 1 | 1 / 1 | 2 / 2 | 2 / 3 | 3 / 3 | 5 / 5 | 6 / 6 | 1 / 2 | 2 / 2 |
| serious Total, serious adverse events | 3 / 10 | 0 / 1 | 0 / 1 | 0 / 2 | 1 / 3 | 2 / 3 | 1 / 5 | 0 / 6 | 0 / 2 | 1 / 2 |
Outcome results
Primary
Spontaneous Annualized Bleeding Rate (sABR)
sABR was derived as \[number of treated bleeds\] / \[duration in years\]. Bleeds with unknown causality were considered as spontaneous. Bleeds were categorized based on the investigator assessment of cause. sABR during the first 12 months of prophylactic treatment with rVWF (vonicog alfa) was reported.
Time frame: Up to 12 months
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) | 1.430 spontaneous bleeds per year | Standard Deviation 2.3894 |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) | 1.040 spontaneous bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) | 0.000 spontaneous bleeds per year | — |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) | 3.022 spontaneous bleeds per year | Standard Deviation 2.4746 |
Secondary
Average Number of Infusions Per Week During Prophylactic Treatment
Average number of infusions per week during prophylactic treatment with rVWF (vonicog alfa) were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Prophylaxis | Average Number of Infusions Per Week During Prophylactic Treatment | 1.87 infusions per week | Standard Deviation 0.351 |
| Cohort 2: Prophylaxis | Average Number of Infusions Per Week During Prophylactic Treatment | 1.01 infusions per week | — |
| Cohort 3: Prophylaxis | Average Number of Infusions Per Week During Prophylactic Treatment | 1.14 infusions per week | — |
| Cohort 4: Prophylaxis | Average Number of Infusions Per Week During Prophylactic Treatment | 1.38 infusions per week | Standard Deviation 0.372 |
Secondary
Change From Baseline in Ferritin Levels Over Time
Change from baseline in ferritin levels over time during prophylactic treatment with rVWF (vonicog alfa) were reported. Baseline Ferritin lab assay for rollover participants in cohorts 1, 2 and 3 were not mandatory per protocol at the Screening Visit of this study as the results from End of Study (EOS) visit of parent studies were expected to be utilized for rollover cohorts 1-3. However, many participants in cohort 1 did not have this data collected at EOS Visit of parent study 071301 and no participant in cohorts 2 and 3 had this data collected at EOS Visit of parent studies 071301 and 071102.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. Overall number of participants analyzed is the number of participants with data available for analyses at Baseline. Number analyzed is the number of participants with data available for analyses at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 6 | 2.0 picomole per liter (pmol/L) | Standard Deviation 2.83 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 18 | 18.0 picomole per liter (pmol/L) | Standard Deviation 46.67 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 2 | 0.0 picomole per liter (pmol/L) | Standard Deviation 1.41 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 21 | 37.5 picomole per liter (pmol/L) | Standard Deviation 64.35 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 9 | 58.5 picomole per liter (pmol/L) | Standard Deviation 91.22 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 24 | 12.0 picomole per liter (pmol/L) | Standard Deviation 26.87 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 3 | -18.5 picomole per liter (pmol/L) | Standard Deviation 21.92 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 27 | 34.0 picomole per liter (pmol/L) | Standard Deviation 60.81 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 12 | 19.0 picomole per liter (pmol/L) | Standard Deviation 26.87 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 30 | 46.5 picomole per liter (pmol/L) | Standard Deviation 77.07 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 1 | 11.0 picomole per liter (pmol/L) | Standard Deviation 18.38 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 33 | 71.5 picomole per liter (pmol/L) | Standard Deviation 106.77 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 15 | 5.5 picomole per liter (pmol/L) | Standard Deviation 13.44 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | End of Study | 38.5 picomole per liter (pmol/L) | Standard Deviation 48.79 |
| Cohort 1: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Baseline | 148.5 picomole per liter (pmol/L) | Standard Deviation 171.83 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | End of Study | -27.6 picomole per liter (pmol/L) | Standard Deviation 52.46 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Baseline | 90.8 picomole per liter (pmol/L) | Standard Deviation 110.82 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 2 | -43.8 picomole per liter (pmol/L) | Standard Deviation 59.6 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 3 | -33.3 picomole per liter (pmol/L) | Standard Deviation 64.57 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 6 | -16.6 picomole per liter (pmol/L) | Standard Deviation 19.88 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 1 | -31.0 picomole per liter (pmol/L) | Standard Deviation 44.89 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 9 | -12.8 picomole per liter (pmol/L) | Standard Deviation 53.05 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 12 | -27.0 picomole per liter (pmol/L) | Standard Deviation 27.51 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 15 | -25.7 picomole per liter (pmol/L) | Standard Deviation 80.16 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 18 | -49.7 picomole per liter (pmol/L) | Standard Deviation 52.56 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 21 | -59.3 picomole per liter (pmol/L) | Standard Deviation 50.16 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 24 | -53.3 picomole per liter (pmol/L) | Standard Deviation 91.22 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 27 | -54.0 picomole per liter (pmol/L) | Standard Deviation 55.56 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 30 | -70.7 picomole per liter (pmol/L) | Standard Deviation 70.12 |
| Cohort 4: Prophylaxis | Change From Baseline in Ferritin Levels Over Time | Month 33 | -21.3 picomole per liter (pmol/L) | Standard Deviation 114 |
Secondary
Number of Infusions of ADVATE
Number of infusions of ADVATE (rFVIII, octocog alfa) utilized to treat BEs during OD treatment while enrolled in the study were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. Overall number of participants analyzed is the number of participants with ADVATE-treated bleeding episodes. Overall number of units analyzed is the number of bleeding episodes treated with ADVATE.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Prophylaxis | Number of Infusions of ADVATE | 1.1 infusions | Standard Deviation 0.25 |
| Cohort 2: Prophylaxis | Number of Infusions of ADVATE | 1.0 infusions | Standard Deviation 0 |
Secondary
Number of Infusions of Vonicog Alfa
Number of infusions of rVWF (vonicog alfa) utilized to treat BEs during OD treatment while enrolled in the study were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. Overall number of units analyzed is the number of bleeding episodes treated with vonicog alfa.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Prophylaxis | Number of Infusions of Vonicog Alfa | 1.1 infusions | Standard Deviation 0.65 |
| Cohort 2: Prophylaxis | Number of Infusions of Vonicog Alfa | 1.2 infusions | Standard Deviation 0.45 |
Secondary
Number of Participants Based on Causality of TEAEs
An AE is defined as any untoward medical occurrence in a participant administered IP that does not necessarily have a causal relationship with the treatment. TEAE was defined as any AE that started after the first administration of study drug in this continuation study. A physician/investigator made the assessment of relationship to investigational product for each AE. Number of participants with TEAEs based on causality were reported.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Based on Causality of TEAEs | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Based on Causality of TEAEs | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Based on Causality of TEAEs | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Based on Causality of TEAEs | 0 Participants |
| Cohort 5: On Demand | Number of Participants Based on Causality of TEAEs | 0 Participants |
| Cohort 6: On Demand | Number of Participants Based on Causality of TEAEs | 0 Participants |
Secondary
Number of Participants Based on Severity of TEAEs
An AE is defined as any untoward medical occurrence in a participant administered IP that does not necessarily have a causal relationship with the treatment. TEAE was defined as any AE that started after the first administration of study drug in this continuation study. Severity of TEAEs was determined by following definitions: Mild: No limitation of usual activities; Moderate: Some limitation of usual activities and may required therapeutic intervention; Severe: Inability to carry out usual activities with sequelae, which required therapeutic intervention. Number of participants with TEAEs based on severity of TEAEs were reported.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Based on Severity of TEAEs | Moderate | 7 Participants |
| Cohort 1: Prophylaxis | Number of Participants Based on Severity of TEAEs | Mild | 7 Participants |
| Cohort 1: Prophylaxis | Number of Participants Based on Severity of TEAEs | Severe | 3 Participants |
| Cohort 2: Prophylaxis | Number of Participants Based on Severity of TEAEs | Moderate | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Based on Severity of TEAEs | Mild | 1 Participants |
| Cohort 2: Prophylaxis | Number of Participants Based on Severity of TEAEs | Severe | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Based on Severity of TEAEs | Moderate | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Based on Severity of TEAEs | Mild | 1 Participants |
| Cohort 3: Prophylaxis | Number of Participants Based on Severity of TEAEs | Severe | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Based on Severity of TEAEs | Moderate | 3 Participants |
| Cohort 4: Prophylaxis | Number of Participants Based on Severity of TEAEs | Mild | 4 Participants |
| Cohort 4: Prophylaxis | Number of Participants Based on Severity of TEAEs | Severe | 1 Participants |
| Cohort 5: On Demand | Number of Participants Based on Severity of TEAEs | Moderate | 11 Participants |
| Cohort 5: On Demand | Number of Participants Based on Severity of TEAEs | Mild | 14 Participants |
| Cohort 5: On Demand | Number of Participants Based on Severity of TEAEs | Severe | 1 Participants |
| Cohort 6: On Demand | Number of Participants Based on Severity of TEAEs | Mild | 2 Participants |
| Cohort 6: On Demand | Number of Participants Based on Severity of TEAEs | Severe | 2 Participants |
| Cohort 6: On Demand | Number of Participants Based on Severity of TEAEs | Moderate | 1 Participants |
Secondary
Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR)
The sABR was the number of spontaneous bleeds divided by the observation period in years, where an observation period = (date of completion/termination-date of first dose+1)/365.2425. sABR was categorized based on number of BEs as 0, greater than (\>) 0 through 2, \>2 through 5, \>5 during the prophylactic treatment with rVWF (vonicog alfa). Bleeding at multiple locations related to the same injury was counted as single BE. BEs of unknown cause were counted as spontaneous bleeds. Number of participants categorized based on sABR during prophylactic treatment with rVWF (vonicog alfa) were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all entry criteria and received any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | 0 bleeds/year | 5 Participants |
| Cohort 1: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >0 to ≤2 bleeds/year | 3 Participants |
| Cohort 1: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >2 to ≤5 bleeds/year | 1 Participants |
| Cohort 1: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >5 bleeds/year | 1 Participants |
| Cohort 2: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >5 bleeds/year | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >2 to ≤5 bleeds/year | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >0 to ≤2 bleeds/year | 1 Participants |
| Cohort 2: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | 0 bleeds/year | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >5 bleeds/year | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >0 to ≤2 bleeds/year | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >2 to ≤5 bleeds/year | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | 0 bleeds/year | 1 Participants |
| Cohort 4: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >5 bleeds/year | 1 Participants |
| Cohort 4: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >0 to ≤2 bleeds/year | 3 Participants |
| Cohort 4: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | 0 bleeds/year | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) | >2 to ≤5 bleeds/year | 1 Participants |
Secondary
Number of Participants Categorized Based on Weekly Number of Infusions
Categorized as ≥ 0 to \< 1 infusion per week, ≥ 1 to \< 2 infusions per week, ≥ 2 to \< 3 infusions per week, ≥ 3 infusions per week. The number of participants categorized based on number of infusions per week during prophylactic treatment with rVWF (vonicog alfa) were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥0 to <1 | 1 Participants |
| Cohort 1: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥2 to <3 | 3 Participants |
| Cohort 1: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥3 | 0 Participants |
| Cohort 1: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥ 1to <2 | 6 Participants |
| Cohort 2: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥2 to <3 | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥ 1to <2 | 1 Participants |
| Cohort 2: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥0 to <1 | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥3 | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥ 1to <2 | 1 Participants |
| Cohort 3: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥2 to <3 | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥0 to <1 | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥3 | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥ 1to <2 | 5 Participants |
| Cohort 4: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥3 | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥2 to <3 | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Categorized Based on Weekly Number of Infusions | ≥0 to <1 | 0 Participants |
Secondary
Number of Participants Who Achieved Transfusion-free Maintenance of Hemoglobin Levels
Transfusion free maintenance of hemoglobin levels during prophylactic treatment with rVWF (vonicog alfa) were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Who Achieved Transfusion-free Maintenance of Hemoglobin Levels | 8 Participants |
| Cohort 2: Prophylaxis | Number of Participants Who Achieved Transfusion-free Maintenance of Hemoglobin Levels | 1 Participants |
| Cohort 3: Prophylaxis | Number of Participants Who Achieved Transfusion-free Maintenance of Hemoglobin Levels | 1 Participants |
| Cohort 4: Prophylaxis | Number of Participants Who Achieved Transfusion-free Maintenance of Hemoglobin Levels | 5 Participants |
Secondary
Number of Participants Who Develop Binding Antibodies to Recombinant Furin (rFurin)
Total Ig antibodies (IgG, IgA, IgM) against human furin were analyzed using ELISA. Number of participants who developed binding antibodies to rFurin were assessed.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Who Develop Binding Antibodies to Recombinant Furin (rFurin) | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Who Develop Binding Antibodies to Recombinant Furin (rFurin) | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Who Develop Binding Antibodies to Recombinant Furin (rFurin) | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Who Develop Binding Antibodies to Recombinant Furin (rFurin) | 0 Participants |
| Cohort 5: On Demand | Number of Participants Who Develop Binding Antibodies to Recombinant Furin (rFurin) | 0 Participants |
| Cohort 6: On Demand | Number of Participants Who Develop Binding Antibodies to Recombinant Furin (rFurin) | 0 Participants |
Secondary
Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins
Total Ig antibodies (IgG, IgA, IgM) against CHO protein were analyzed using ELISA. Number of participants who developed binding antibodies to CHO proteins were assessed.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins | 0 Participants |
| Cohort 5: On Demand | Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins | 0 Participants |
| Cohort 6: On Demand | Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins | 0 Participants |
Secondary
Number of Participants Who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG)
Detection and quantification of IgG antibodies originating from human plasma that were directed against mouse-IgG (HAMA: human anti- mouse antibodies) were assessed using ELISA (Medac, Hamburg, Germany). Number of participants who developed binding antibodies to Mouse IgG were assessed.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG) | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG) | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG) | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG) | 0 Participants |
| Cohort 5: On Demand | Number of Participants Who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG) | 0 Participants |
| Cohort 6: On Demand | Number of Participants Who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG) | 0 Participants |
Secondary
Number of Participants Who Developed Neutralizing Antibodies to Factor VIII (FVIII)
Three functional VWF assays for von Willebrand factor collagen binding (VWF:CB), von Willebrand factor: Ristocetin Cofactor (VWF:RCo) and von Willebrand factor VIII B (VWF:FVIIIB) were used to test the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and VWF:FVIIIB activities was measured by assays based on the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the Bethesda assay). Only confirmed neutralizing anti -VWF antibodies were considered inhibitors. Number of participants who developed neutralizing antibodies to FVIII were assessed.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Who Developed Neutralizing Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Who Developed Neutralizing Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Who Developed Neutralizing Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Who Developed Neutralizing Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 5: On Demand | Number of Participants Who Developed Neutralizing Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 6: On Demand | Number of Participants Who Developed Neutralizing Antibodies to Factor VIII (FVIII) | 0 Participants |
Secondary
Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (VWF)
Three functional VWF assays for von Willebrand factor collagen binding (VWF:CB), von Willebrand factor: Ristocetin Cofactor (VWF:RCo) and von Willebrand factor VIII B (VWF:FVIIIB) were used to test the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and VWF:FVIIIB activities were measured by assays based on the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the Bethesda assay). Only confirmed neutralizing anti -VWF antibodies were considered inhibitors. Number of participants who developed neutralizing antibodies to rVWF were assessed.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 5: On Demand | Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 6: On Demand | Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
Secondary
Number of Participants Who Developed Total Binding Antibodies to Factor VIII (FVIII)
Binding antibodies against FVIII were analyzed using a proprietary enzyme immunoassay. Number of participants who developed of total binding antibodies to FVIII were assessed.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Who Developed Total Binding Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Who Developed Total Binding Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Who Developed Total Binding Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Who Developed Total Binding Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 5: On Demand | Number of Participants Who Developed Total Binding Antibodies to Factor VIII (FVIII) | 1 Participants |
| Cohort 6: On Demand | Number of Participants Who Developed Total Binding Antibodies to Factor VIII (FVIII) | 0 Participants |
Secondary
Number of Participants Who Developed Total Binding Antibodies to Von Willebrand Factor (VWF)
The presence of total binding anti-VWF antibodies was determined by an enzyme-linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin (Ig) antibodies (IgG, IgM and IgA). Number of participants who developed of total binding antibodies to rVWF were assessed.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants Who Developed Total Binding Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants Who Developed Total Binding Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants Who Developed Total Binding Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants Who Developed Total Binding Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 5: On Demand | Number of Participants Who Developed Total Binding Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
| Cohort 6: On Demand | Number of Participants Who Developed Total Binding Antibodies to Von Willebrand Factor (VWF) | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes in Laboratory Parameters
Clinical laboratory parameters included serum chemistry, hematology and urinalysis assessments. Number of participants with clinically significant change from baseline in clinical laboratory parameters were assessed.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Hematology | 0 Participants |
| Cohort 1: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Serum Chemistry | 0 Participants |
| Cohort 1: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Urinalysis | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Hematology | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Serum Chemistry | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Urinalysis | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Hematology | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Serum Chemistry | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Urinalysis | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Hematology | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Serum Chemistry | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Urinalysis | 0 Participants |
| Cohort 5: On Demand | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Hematology | 0 Participants |
| Cohort 5: On Demand | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Serum Chemistry | 0 Participants |
| Cohort 5: On Demand | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Urinalysis | NA Participants |
| Cohort 6: On Demand | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Serum Chemistry | 0 Participants |
| Cohort 6: On Demand | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Urinalysis | NA Participants |
| Cohort 6: On Demand | Number of Participants With Clinically Significant Changes in Laboratory Parameters | Hematology | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes in Vital Signs
Vital signs included blood pressure (systolic and diastolic), pulse rate, respiratory rate and body temperature. Number of participants with clinically significant change from baseline in vital signs were assessed.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants With Clinically Significant Changes in Vital Signs | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants With Clinically Significant Changes in Vital Signs | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants With Clinically Significant Changes in Vital Signs | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants With Clinically Significant Changes in Vital Signs | 0 Participants |
| Cohort 5: On Demand | Number of Participants With Clinically Significant Changes in Vital Signs | 0 Participants |
| Cohort 6: On Demand | Number of Participants With Clinically Significant Changes in Vital Signs | 0 Participants |
Secondary
Number of Participants With Hypersensitivity Reactions
Hypersensitivity (also called hypersensitivity reaction or intolerance) defined as undesirable reactions produced by the normal immune system, including allergies and autoimmunity. Potential hypersensitivity events were identified by broad search criteria and then medically assessed. Number of participants with hypersensitivity reactions as TEAEs of special interest was calculated.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants With Hypersensitivity Reactions | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants With Hypersensitivity Reactions | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants With Hypersensitivity Reactions | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants With Hypersensitivity Reactions | 0 Participants |
| Cohort 5: On Demand | Number of Participants With Hypersensitivity Reactions | 0 Participants |
| Cohort 6: On Demand | Number of Participants With Hypersensitivity Reactions | 0 Participants |
Secondary
Number of Participants With Thromboembolic Events
Thromboembolism defined as formation of a clot (thrombus) in a blood vessel that breaks loose, is carried by the blood stream and could plug another vessel. Number of participants with thromboembolic events as TEAEs of special interest were reported.
Time frame: Up to 5.8 years
Population: The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants With Thromboembolic Events | 0 Participants |
| Cohort 2: Prophylaxis | Number of Participants With Thromboembolic Events | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants With Thromboembolic Events | 0 Participants |
| Cohort 4: Prophylaxis | Number of Participants With Thromboembolic Events | 0 Participants |
| Cohort 5: On Demand | Number of Participants With Thromboembolic Events | 0 Participants |
| Cohort 6: On Demand | Number of Participants With Thromboembolic Events | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE): any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to medicinal product. TEAE was defined as any AE that started after the first administration of study drug in this continuation study. Serious TEAEs: any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is medically important.
Time frame: Up to 5.8 years
Population: The Safety Analysis Set (SAS) consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 8 Participants |
| Cohort 1: Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 3 Participants |
| Cohort 2: Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 1 Participants |
| Cohort 2: Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
| Cohort 3: Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 1 Participants |
| Cohort 4: Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 4 Participants |
| Cohort 4: Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 1 Participants |
| Cohort 5: On Demand | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 15 Participants |
| Cohort 5: On Demand | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 3 Participants |
| Cohort 6: On Demand | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 1 Participants |
| Cohort 6: On Demand | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 2 Participants |
Secondary
Overall Hemostatic Efficacy Rating
Overall Hemostatic Efficacy Rating at resolution of bleed with respect to treatment of BEs for initial 12 months of study in OD cohorts. Hemostatic efficacy for treatment of BEs was rated on 4-point Likert scale as:excellent=full relief of pain&cessation of objective signs of bleeding after single infusion,no additional infusion is required for control of bleeding&administration of further infusion to maintain hemostasis would not affect scoring;good=definite pain relief&/or improvement in signs of bleeding after single infusion,possibly requires \>2 infusions for complete resolution&administration of further infusion to maintain hemostasis would not affect scoring;fair=probable&/or slight relief of pain&slight improvement in signs of bleeding after single infusion,required multiple infusions for complete resolution;none=no improvement of signs/symptoms or conditions worsen.Missing=number of unique BEs without any overall hemostatic efficacy rating at resolution of breakthrough BE.
Time frame: Initial 12 months of study
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. Overall number of participants analyzed is the number of participants with treated bleeding episodes and overall number of units analyzed is the number of bleeding episodes treated in the initial 12 months of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Prophylaxis | Overall Hemostatic Efficacy Rating | Good | 1 bleeding episodes |
| Cohort 1: Prophylaxis | Overall Hemostatic Efficacy Rating | None | 0 bleeding episodes |
| Cohort 1: Prophylaxis | Overall Hemostatic Efficacy Rating | Fair | 0 bleeding episodes |
| Cohort 1: Prophylaxis | Overall Hemostatic Efficacy Rating | Missing | 1 bleeding episodes |
| Cohort 1: Prophylaxis | Overall Hemostatic Efficacy Rating | Excellent | 74 bleeding episodes |
| Cohort 2: Prophylaxis | Overall Hemostatic Efficacy Rating | Missing | 3 bleeding episodes |
| Cohort 2: Prophylaxis | Overall Hemostatic Efficacy Rating | Excellent | 21 bleeding episodes |
| Cohort 2: Prophylaxis | Overall Hemostatic Efficacy Rating | Good | 0 bleeding episodes |
| Cohort 2: Prophylaxis | Overall Hemostatic Efficacy Rating | Fair | 0 bleeding episodes |
| Cohort 2: Prophylaxis | Overall Hemostatic Efficacy Rating | None | 0 bleeding episodes |
Secondary
Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding
sABR was derived as \[number of treated bleeds\] / \[duration in years\]. sABR for BEs based on location of bleeding: Skin, Muscle, Mucosal Nasal, Mucosal Oral, Joint, Gastrointestinal (GI), Menstrual/Heavy Menstrual, Venipuncture Site, Soft Tissue, Body Cavity, Hematuria, Central Nervous System (CNS) and Other, while on prophylactic treatment with rVWF (vonicog alfa) were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all entry criteria and received any amount of study drug. Number analyzed is the number of participants with data available for analyses for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | GI | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | CNS | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Mucosal, Nasal | 0.199 bleeds per year | Standard Deviation 0.3542 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Body Cavity | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Menstrual/Heavy Menstrual | 2.770 bleeds per year | Standard Deviation 3.9174 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Mucosal, Oral | 0.268 bleeds per year | Standard Deviation 0.7358 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Hematuria | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Venipuncture Site | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Other | 0.067 bleeds per year | Standard Deviation 0.1413 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Skin | 0.033 bleeds per year | Standard Deviation 0.1044 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Joint | 0.067 bleeds per year | Standard Deviation 0.2119 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Soft Tissue | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Muscle | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Soft Tissue | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Hematuria | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Other | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Skin | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Mucosal, Oral | 0.330 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | CNS | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Body Cavity | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | GI | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Menstrual/Heavy Menstrual | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Joint | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Venipuncture Site | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Mucosal, Nasal | 0.000 bleeds per year | — |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Muscle | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Body Cavity | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Skin | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Mucosal, Nasal | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Mucosal, Oral | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | GI | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Venipuncture Site | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Other | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Muscle | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Joint | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Soft Tissue | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Hematuria | 0.000 bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | CNS | 0.000 bleeds per year | — |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Menstrual/Heavy Menstrual | 0.500 bleeds per year | Standard Deviation 0.7071 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Mucosal, Nasal | 0.068 bleeds per year | Standard Deviation 0.1521 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Muscle | 0.068 bleeds per year | Standard Deviation 0.1521 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Soft Tissue | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | GI | 0.136 bleeds per year | Standard Deviation 0.3041 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Joint | 1.370 bleeds per year | Standard Deviation 2.3644 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Mucosal, Oral | 0.268 bleeds per year | Standard Deviation 0.5993 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | CNS | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Skin | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Other | 0.068 bleeds per year | Standard Deviation 0.1521 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Body Cavity | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Hematuria | 0.000 bleeds per year | Standard Deviation 0 |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding | Venipuncture Site | 0.000 bleeds per year | Standard Deviation 0 |
Secondary
Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment
sABR was derived as \[number of treated bleeds\] / \[duration in years\]. Bleeds with unknown causality were considered as spontaneous. Bleeds were categorized based on the investigator assessment of cause. sABR during prophylaxis treatment with rVWF (vonicog alfa) while enrolled in the study were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment | 1.122 spontaneous bleeds per year | Standard Deviation 2.1084 |
| Cohort 2: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment | 0.330 spontaneous bleeds per year | — |
| Cohort 3: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment | 0.000 spontaneous bleeds per year | — |
| Cohort 4: Prophylaxis | Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment | 2.110 spontaneous bleeds per year | Standard Deviation 1.9954 |
Secondary
Time to First Bleeding Event on Prophylaxis Treatment
Time to event estimates and confidence intervals obtained from Kaplan-Meier analysis. Participants with 0 bleeds during each study period were censored at the date of the last day in that study period.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all entry criteria and received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Prophylaxis | Time to First Bleeding Event on Prophylaxis Treatment | 172 days |
| Cohort 2: Prophylaxis | Time to First Bleeding Event on Prophylaxis Treatment | 141 days |
| Cohort 3: Prophylaxis | Time to First Bleeding Event on Prophylaxis Treatment | NA days |
| Cohort 4: Prophylaxis | Time to First Bleeding Event on Prophylaxis Treatment | 88 days |
Secondary
Total Number of Infusions During Prophylactic Treatment
Total number of infusions during prophylactic treatment with rVWF (vonicog alfa) were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Prophylaxis | Total Number of Infusions During Prophylactic Treatment | 287.8 infusions | Standard Deviation 53.42 |
| Cohort 2: Prophylaxis | Total Number of Infusions During Prophylactic Treatment | 157.0 infusions | — |
| Cohort 3: Prophylaxis | Total Number of Infusions During Prophylactic Treatment | 177.0 infusions | — |
| Cohort 4: Prophylaxis | Total Number of Infusions During Prophylactic Treatment | 159.2 infusions | Standard Deviation 41.55 |
Secondary
Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment
For each participant, the body weight-adjusted dose (IU/kg) was derived as the number of units of rVWF infused (IU) divided by the last available body weight (kilogram \[kg\]) prior to the infusion. Total weight adjusted consumption of rVWF (vonicog alfa) per participant during prophylactic treatment with rVWF (vonicog alfa) was reported as International Units per kilogram (IU/kg).
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Prophylaxis | Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment | 14953.497 IU/kg | Standard Deviation 3349.4461 |
| Cohort 2: Prophylaxis | Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment | 9992.460 IU/kg | — |
| Cohort 3: Prophylaxis | Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment | 9270.620 IU/kg | — |
| Cohort 4: Prophylaxis | Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment | 9171.746 IU/kg | Standard Deviation 1505.5667 |
Secondary
Weight-adjusted Consumption of ADVATE Per Bleeding Episode
Weight-adjusted consumption (IU/kg) was derived as the total units infused (IU) divided by the last available body weight (kg) prior to the infusion. Weight-adjusted consumption of ADVATE (rFVIII, octocog alfa) per bleeding episode during OD treatment while enrolled in the study were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. Overall number of participants analyzed is the number of participants with ADVATE-treated bleeding episodes. Overall number of units analyzed is the number of bleeding episodes treated with ADVATE.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Prophylaxis | Weight-adjusted Consumption of ADVATE Per Bleeding Episode | 39.217 IU/kg per bleeding episode | Standard Deviation 11.0752 |
| Cohort 2: Prophylaxis | Weight-adjusted Consumption of ADVATE Per Bleeding Episode | 35.175 IU/kg per bleeding episode | Standard Deviation 2.2274 |
Secondary
Weight-adjusted Consumption of Vonicog Alfa Per Bleeding Episode
Weight-adjusted consumption (IU/kg) was derived as the total units infused (IU) divided by the last available body weight (kg) prior to the infusion. Weight-adjusted consumption of rVWF (vonicog alfa) per bleeding episode during OD treatment while enrolled in the study were reported.
Time frame: Up to 5.8 years
Population: The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. Overall number of units analyzed is the number of bleeding episodes treated with vonicog alfa and had consumption data available for analysis of this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Prophylaxis | Weight-adjusted Consumption of Vonicog Alfa Per Bleeding Episode | 56.109 IU/kg per bleeding episode | Standard Deviation 33.1312 |
| Cohort 2: Prophylaxis | Weight-adjusted Consumption of Vonicog Alfa Per Bleeding Episode | 61.713 IU/kg per bleeding episode | Standard Deviation 26.6936 |